Abstract CT108: Beamion LUNG-1 and LUNG-2: The zongertinib clinical program in patients with advanced <i>HER2-</i>mutant non-small cell lung cancer

Abstract Background: There is an unmet need for more effective treatment options for HER2-mutant non-small cell lung cancer (NSCLC), necessitating the development of targeted treatments. Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing epidermal growth factor receptor, thereby limiting associated toxicities. The Beamion LUNG-1 phase 1a dose-escalation trial enrolled patients with advanced, unresectable, or metastatic solid tumors with HER2 alterations, refractory to/unsuitable for conventional treatment, or who exhausted treatment options. Preliminary results demonstrate that zongertinib exhibits promising antitumor activity with a manageable safety profile. This abstract describes the subgroups and endpoints of the ongoing Beamion LUNG-1 (phase 1b; NCT04886804) and Beamion LUNG-2 (phase 3; NCT06151574) trials. Methods: Phase 1b of Beamion LUNG-1 is a dose-expansion study evaluating early efficacy of zongertinib in patients with NSCLC with or without prior treatment. Pretreated patients with advanced NSCLC with tumors harboring a HER2 tyrosine kinase domain (TKD) mutation were first enrolled (cohort 1); the study was later expanded to include more cohorts: Treatment-naïve NSCLC with HER2 TKD mutations (2), NSCLC with non-TKD HER2 mutations (3), NSCLC with HER2 TKD mutations and active brain metastases (4), NSCLC with HER2 TKD mutations and prior treatment with platinum-based chemotherapy ± immunotherapy followed by a HER2-directed antibody-drug conjugate (5), and NSCLC with HER2 TKD mutations and prior systemic therapy based in the United States (6, open for enrollment). The primary endpoint is objective response rate (ORR, per RECIST v1.1). Beamion LUNG-2 will evaluate treatment-naïve patients with advanced or metastatic non-squamous NSCLC harboring TKD HER2 mutations, comparing the efficacy/safety of zongertinib with the standard of care (pembrolizumab plus platinum-based chemotherapy [cisplatin/carboplatin and pemetrexed]). The primary endpoint is progression-free survival (RECIST v1.1 assessed by blinded independent centralized review). Key secondary endpoints include overall survival, ORR, duration of response, and patient-reported outcomes. Citation Format: Yi-Long Wu, Frans Opdam, Noboru Yamamoto, Tatsuya Yoshida, John Heymach. Beamion LUNG-1 and LUNG-2: The zongertinib clinical program in patients with advanced HER2-mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT108.